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1.
Changsung Kim 《BMB reports》2015,48(5):256-265
Cardiovascular and neurodegenerative diseases are major health threats in many
developed countries. Recently, target tissues derived from human embryonic stem
(hES) cells and induced pluripotent stem cells (iPSCs), such as cardiomyocytes
(CMs) or neurons, have been actively mobilized for drug screening. Knowledge of
drug toxicity and efficacy obtained using stem cell-derived tissues could
parallel that obtained from human trials. Furthermore, iPSC disease models could
be advantageous in the development of personalized medicine in various parts of
disease sectors. To obtain the maximum benefit from iPSCs in disease modeling,
researchers are now focusing on aging, maturation, and metabolism to
recapitulate the pathological features seen in patients. Compared to pediatric
disease modeling, adult-onset disease modeling with iPSCs requires proper
maturation for full manifestation of pathological features. Herein, the success
of iPSC technology, focusing on patient-specific drug treatment,
maturation-based disease modeling, and alternative approaches to compensate for
the current limitations of patient iPSC modeling, will be further discussed.
[BMB Reports 2015; 48(5): 256-265] 相似文献
2.
Understanding of the ecology of infected animals facilitates disease risk assessment and is also crucial for wildlife conservation. Relatively little is known about the spatial distribution of infected wild mammals in relation to environmental factors. In neighboring Mediterranean ecosystems 250 European brown hares (Lepus europaeus) were collected and examined with RT-PCR to detect European Brown Hare Syndrome Virus (EBHSV). Multivariate statistics and Geographical Information System (GIS) analysis were applied to estimate spatial patterns of biotic and abiotic factors and human activities as determinants of EBHSV positivity. Hare population abundance was estimated using faeces counts and belt drive censuses. The study showed that EBHSV infected hares had widespread distribution even in isolated areas. However, EBHSV infection prevalence was higher in areas with higher hare abundance, closer to paved road networks and at lower altitudes. The risk map revealed the potential distribution of EBHSV-infected hares. This study shows that host abundance and landscape influence the ecology of the disease, a finding that should be taken into account in future studies. The management of harvest and restocking of hares is also discussed for population conservation. 相似文献
3.
Amaria Darmellah Amel Rayah Rodolphe Auger Marie-Hélène Cuif Magali Prigent Monique Arpin Andres Alcover Cécile Delarasse Jean M. Kanellopoulos 《The Journal of biological chemistry》2012,287(41):34583-34595
The amyloid precursor protein (APP) can be cleaved by α-secretases in neural cells to produce the soluble APP ectodomain (sAPPα), which is neuroprotective. We have shown previously that activation of the purinergic P2X7 receptor (P2X7R) triggers sAPPα shedding from neural cells. Here, we demonstrate that the activation of ezrin, radixin, and moesin (ERM) proteins is required for the P2X7R-dependent proteolytic processing of APP leading to sAPPα release. Indeed, the down-regulation of ERM by siRNA blocked the P2X7R-dependent shedding of sAPPα. We also show that P2X7R stimulation triggered the phosphorylation of ERM. Thus, ezrin translocates to the plasma membrane to interact with P2X7R. Using specific pharmacological inhibitors, we established the order in which several enzymes trigger the P2X7R-dependent release of sAPPα. Thus, a Rho kinase and the MAPK modules ERK1/2 and JNK act upstream of ERM, whereas a PI3K activity is triggered downstream. For the first time, this work identifies ERM as major partners in the regulated non-amyloidogenic processing of APP. 相似文献
4.
Philip K. Frykman Erik H. Lindsley Mark Gaon Daniel L. Farkas 《Journal of biophotonics》2008,1(2):97-103
We used advanced spectral imaging for intrasurgical decision making in a preclinical study, on a mouse model of Hirschsprung's Disease. Our imaging device sampled areas from normal and abnormal (aganglionic) colon in these animals. Spectral segmentation and classification of the resulting images showed a clear distinction between the normal and aganglionic regions, as confirmed by pathological analysis and use of mutant mice. We developed a simple algorithm that could distinguish normal from aganglionic colon with high spatial resolution and reproducibility, and the following statistics: sensitivity = 97%, specificity = 94%, positive predictive value = 92%, negative predictive value = 98%. These studies showed translational proof of concept that spectral imaging could be used during operations, in real time, to help surgeons precisely distinguish normal from abnormal tissue without requiring traditional biopsy. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) 相似文献
5.
Two hundred black and white adult human skeletons and 200 living black and white children from the greater Cleveland area were examined for evidence of enamel hypoplasia. Enamel hypoplasia, present in varying expressings (pits, lines and grooves), was found to be more prevalent in both skeletal samples, than in the living groups. In the majority of cases, sex differences between white and black males and females through time and space are highly significant for all tooth catagories. Regardless of the mechanisms behind it, prevalence of enamel hypoplasia for both white and black group has significantly declined through time. No evidence suggesting specific etiologies responsible for enamel hypoplasia can be found. In the majority of previously published reports, the etiology is still idiopathic. The reduction in the prevalence of enamel hypoplasia in the groups examined through time may be related to improved nutritional conditions and the elimination or decline of childhood diseases that have been implicated in this condition. 相似文献
6.
Franck Debeurme Antoine Picciocchi Marie-Claire Dagher Didier Grunwald Sylvain Beaumel Franck Fieschi Marie-José Stasia 《The Journal of biological chemistry》2010,285(43):33197-33208
The X+-linked chronic granulomatous disease (X+-CGD) variants are natural mutants characterized by defective NADPH oxidase activity but with normal Nox2 expression. According to the three-dimensional model of the cytosolic Nox2 domain, most of the X+-CGD mutations are located in/or close to the FAD/NADPH binding regions. A structure/function study of this domain was conducted in X+-CGD PLB-985 cells exactly mimicking 10 human variants: T341K, C369R, G408E, G408R, P415H, P415L, Δ507QKT509-HIWAinsert, C537R, L546P, and E568K. Diaphorase activity is defective in all these mutants. NADPH oxidase assembly is normal for P415H/P415L and T341K mutants where mutation occurs in the consensus sequences of NADPH- and FAD-binding sites, respectively. This is in accordance with their buried position in the three-dimensional model of the cytosolic Nox2 domain. FAD incorporation is abolished only in the T341K mutant explaining its absence of diaphorase activity. This demonstrates that NADPH oxidase assembly can occur without FAD incorporation. In addition, a defect of NADPH binding is a plausible explanation for the diaphorase activity inhibition in the P415H, P415L, and C537R mutants. In contrast, Cys-369, Gly-408, Leu-546, and Glu-568 are essential for NADPH oxidase complex assembly. However, according to their position in the three-dimensional model of the cytosolic domain of Nox2, only Cys-369 could be in direct contact with cytosolic factors during oxidase assembly. In addition, the defect in oxidase assembly observed in the C369R, G408E, G408R, and E568K mutants correlates with the lack of FAD incorporation. Thus, the NADPH oxidase assembly process and FAD incorporation are closely related events essential for the diaphorase activity of Nox2. 相似文献
7.
8.
William F. Schwindinger Lauren J. Murphree Mihalcik Kathryn E. Giger Kelly S. Betz Anna Maria Stauffer Joel Linden Denis Herve Janet D. Robishaw 《The Journal of biological chemistry》2010,285(39):29787-29796
The adenosine A2A receptor (A2AR) is increasingly recognized as a novel therapeutic target in Parkinson disease. In striatopallidal neurons, the G-protein αolf subtype is required to couple this receptor to adenylyl cyclase activation. It is now well established that the βγ dimer also performs an active role in this signal transduction process. In principal, sixty distinct βγ dimers could arise from combinatorial association of the five known β and 12 γ subunit genes. However, key questions regarding which βγ subunit combinations exist and whether they perform specific signaling roles in the context of the organism remain to be answered. To explore these questions, we used a gene targeting approach to specifically ablate the G-protein γ7 subtype. Revealing a potentially new signaling paradigm, we show that the level of the γ7 protein controls the hierarchial assembly of a specific G-protein αolfβ2γ7 heterotrimer in the striatum. Providing a probable basis for the selectivity of receptor signaling, we further demonstrate that loss of this specific G-protein heterotrimer leads to reduced A2AR activation of adenylyl cyclase. Finally, substantiating an important role for this signaling pathway in pyschostimulant responsiveness, we show that mice lacking the G-protein γ7 subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A2AR G-protein αolfβ2γ7 interface as a possible therapeutic target for Parkinson disease. 相似文献
9.
《Fungal biology》2020,124(1):44-53
Alternaria blight is one of the most devastating diseases of rapeseed-mustard caused by a necrotrophic fungus Alternaria brassicae. Lack of satisfactory resistance resource in Brassica is still a main obstruction for developing resistance against Alternaria. In this study, we have selected Brassica juncea, Sinapis alba and Camelina sativa to understand and unravel the mechanism of disease resistance against Alternaria. Histopathological studies showed early onset of necrosis in B. juncea (1 dpi) and delayed in S. alba (2 dpi) and C. sativa (3 dpi) respectively. Early and enhanced production of hydrogen peroxide (H2O2) was observed in C. sativa and S. alba (6 hpi) when compared to B. juncea (12 hpi). An increase in catalase activity was observed in both C. sativa (36 % at 6 hpi) and S. alba (15 % at 12 hpi), whereas it significantly decreased in B. juncea at 6 hpi (23 %), 12 hpi (30 %) and 24 hpi (8 %). Gene expression analysis showed induction of PR-3 and PR-12 genes only in C. sativa and S. alba when compared to B. juncea suggesting their vital role for Alternaria resistance. In contrast, SA marker genes were significantly expressed in B. juncea only which provides evidence of hormonal cross talk in B. juncea during Alternaria infection thereby increasing its susceptibility. 相似文献
10.
Shahin Zibaee Graham Fraser Ross Jakes David Owen Louise C. Serpell R. Anthony Crowther Michel Goedert 《The Journal of biological chemistry》2010,285(49):38555-38567
Filamentous inclusions made of α-synuclein are found in nerve cells and glial cells in a number of human neurodegenerative diseases, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. The assembly and spreading of these inclusions are likely to play an important role in the etiology of common dementias and movement disorders. Both α-synuclein and the homologous β-synuclein are abundantly expressed in the central nervous system; however, β-synuclein is not present in the pathological inclusions. Previously, we observed a poor correlation between filament formation and the presence of residues 73–83 of α-synuclein, which are absent in β-synuclein. Instead, filament formation correlated with the mean β-sheet propensity, charge, and hydrophilicity of the protein (global physicochemical properties) and β-strand contiguity calculated by a simple algorithm of sliding averages (local physicochemical property). In the present study, we rendered β-synuclein fibrillogenic via one set of point mutations engineered to enhance global properties and a second set engineered to enhance predominantly β-strand contiguity. Our findings show that the intrinsic physicochemical properties of synucleins influence their fibrillogenic propensity via two distinct but overlapping modalities. The implications for filament formation and the pathogenesis of neurodegenerative diseases are discussed. 相似文献